The present invention relates to a melt-formulated, multiparticulate, oral dosage form containing clavulanic acid and/or one or more of the physiologically acceptable salts thereof and one or more sucrose fatty acid esters and optionally further physiologically acceptable auxiliary substances, to a process for the production thereof and to the use thereof.
Clavulanic acid, in particular in the form of potassium clavulanate, is frequently used in combination with a β-lactam antibiotic, such as for example amoxicillin, for the treatment of bacterial infections by Gram negative and Gram positive β-lactam-resistant pathogens. Due to the combination with clavulanic acid, which is capable of cleaving β-lactamases, these pathogens, despite initial resistance, again become sensitive to treatment with amoxicillin. This combination is used inter alia for the treatment of otitis media in children. Treatment involves the administration of different dose combinations of clavulanic acid to amoxicillin, with ratios of 1:4, 1:7 or 1:8 being the most common.
One major problem in the production of pharmaceutical preparations comprising clavulanate, preferably potassium clavulanate, is this compound's high susceptibility to hydrolysis. Even over the course of processing and storage of the compound under normal conditions (ambient temperature of 25° C. and 60% relative atmospheric humidity), increasing hydrolysis of the clavulanic acid occurs within a few hours to days, this being accompanied by an intense discoloration and release of CO2.
Decomposition of the compound is accelerated as temperature and humidity increase and furthermore proceeds autocatalytically, a cascade of different decomposition products possibly arising. This decomposition is described in greater detail in WO 94/16696.
As a consequence of this susceptibility to hydrolysis, when processing potassium clavulanate, which is conventionally already commercially available as a mixture with a grade of microcrystalline cellulose which is in a particularly desiccated form or with dry silicon dioxide, it is necessary both to exclude moisture (relative atmospheric humidity of the direct surroundings of less than 20%) and to keep the room or ambient temperature below 20° C.
Already known powders for suspension and film coated tablets are thus based on powder mixtures with silicon dioxide or on a dry compacted form of the clavulanate, wherein the auxiliary substances used must also be dried before use. When coating the tablets with a film, special low-moisture processes are used, as are for example described in WO 95/28927.
Since pellets are conventionally produced using aqueous solutions or with the assistance of lipophilic matrix materials, such a formulation method is not suitable for formulating mixtures containing clavulanate to yield pellets. Due to clavulanate's susceptibility to moisture, no aqueous solutions can be used and, due to the delaying action on active ingredient release which conventionally occurs, no lipophilic matrix materials may be used either. This is in particular contrary to the therapeutic goal, according to which rapid release and availability in the body are to be achieved.